Mycobacterium tuberculosis (Mtb) resistant to current first-line antibacterial agents is a serious and growing public health threat, causing nearly 500,000 new tuberculosis (TB) cases and 170,000 deaths annually. Treatments for drug-sensitive disease are lengthy, complex, and patient noncompliance exacerbates the development of drug-resistant (DR) TB cases, for which treatments are even more prolonged, toxic, expensive, and have lower cure rates. The current proposal is designed to develop an innovative combination regimen using an existing second line drug, Capreomycin, a new class of superior bactericidal antibiotic, Sutezolid, and a candidate therapeutic vaccine delivered as an inhaled product that offers significant potential to improve treatment of DR-TB. An effective treatment that targets both the pathogen and boosts the host immune response to accelerate bacterial clearance, prevent relapse, and shorten therapy, would play an important role in dramatically reducing the impact of the Mtb pathogen. We will leverage the strength of proprietary vaccine adjuvants, and a clinical stage vaccine antigen, ID93, that has entered Phase 2 human clinical testing. This application is an extension of our systematic and methodical approach towards controlling TB. Over the last twenty years, we have applied this strategy towards developing viable vaccine candidates such as M72/AS01E and ID93/GLA- SE (both in clinical stage testing). At present, to our knowledge, ID93/GLA-SE is the sole TB vaccine candidate in the pipeline that has been tested for efficacy against DR-TB, as well as for prophylaxis and therapy in multiple animal models of TB. Funding this R01 project to develop a candidate therapeutic vaccine used as adjunctive treatment with drugs for DR-TB will address this global infectious disease threat.